The mammalian immune system provides a springboard for much of modern medicine through its ability to raise a specific response against undesirable targets in the body. However, there are other conditions where the immune response is undesirable, e.g. in transplantation, allergy and in the context of autoimmune disease. While T cells orchestrate the immune response, they do not effectively respond to antigen unless the antigen is processed and presented to them by the appropriate antigen presenting cells. The 3 major classes of antigen presenting cells are dendritic cells (DCs), macrophages, and B cells, but dendritic cells are considerably more potent on a cell-to-cell basis.
DC precursors migrate from bone marrow and circulate in the blood to specific sites in the body, where they mature. This trafficking is directed by expression of chemokine receptors and adhesion molecules. Upon exposure to antigen and activation signals, the DCs are activated, and leave tissues to migrate via the afferent lymphatics to the T cell rich paracortex of the draining lymph nodes. The activated DCs then secrete chemokines and cytokines involved in T cell homing and activation, and present processed antigen to T cells. This link between DC traffic pattern and functions has led to the investigation of the chemokine responsiveness of DCs during their development and maturation. Chemokines are a subclass of cytokines, which have distinct structural features and biological effects. Their primary activity appears to be on the chemotaxis of leukocytes. All chemokines bind to members of a G-protein coupled serpentine receptor superfamily that span the leukocyte cell surface membrane seven times (7-TM). A review of known chemokines may be found in Rossi (2000) Annual Review of Immunology 18:217-42. For a review of the effect of chemokines on DC subsets, see Dieu-Nosjean (1999) J. Leuk. Biol. 66(2):252-62.
DCs mature by upregulating costimulatory molecules (CD40, CD80 and CD86), and migrate to T cell areas of organized lymphoid tissues where they activate naive T cells and induce effector rather than tolerogenic immune responses. In the absence of such inflammatory or infectious signals, however, DCs present self-antigens in secondary lymphoid tissues for the induction and maintenance of self-tolerance. The ability of DCs to induce tolerance has led to numerous studies using these cells therapeutically in an effort to control unwanted immune responses in models of allograft rejection, graft-versus-host disease (GVHD) and autoimmune disorders. Most studies have employed myeloid DCs (mDCs) derived from mouse bone marrow or human monocytes cultured in vitro using the cytokines granulocyte-macrophage colony stimulating factor (GM-CSF) in the presence or absence of interleukin 4 (IL-4).
For example, in vitro derived immature mDCs were able to dampen arthritis in an antigen-driven mouse model or prolong allograft survival in a murine transplant model. See Martin et al. (2002) Blood 100:383-390; Hoffmann et al. (2002) J Exp Med 196:389-399; Cohen et al. (2002) J Exp Med 196:401-406; van Duivenvoorde et al. (2006) Immunobiology 211:627-632; and Morelli and Thomson (2007) Nat Rev Immunol 7:610-621. Some studies have further manipulated mDCs through genetic modification or exposure to either immunosuppressive agents, or cytokines such as IL-10 and transforming growth factor-β (TGF-β) in an effort to generate more potent tolerogenic mDC populations. Recent studies suggest that lymphoid-related CD11c+ CD8α+ DCs, mobilized in vivo by the hematopoietic growth factor fms-like tyrosine kinase 3 ligand (Flt3L), may prolong the survival of vascularized heart allografts in rodents.
Plasmacytoid DCs are best known for their high production amounts of type I interferons and subsequent induction of cell-mediated adaptive immune responses after viral activation, although freshly isolated pDCs, in the absence of maturation signals, do not induce strong T cell responses (see Gilliet et al. (2002) J Exp Med 195:953-958; Chen et al. (2004) Blood 103:2547-2553; Arpinati et al. (2003) Transpl Immunol 11, 345-356).
In spite of the promise of cellular therapy with DC populations, to date no studies have taken advantage of specific tolerogenic phenotypes to sort immunosuppressive from immune activating DCs. Perhaps as a consequence, most DC populations studied have yielded only partial or transient amelioration of autoimmune symptoms or allograft survival. Methods for tolerization with biologically relevant cell populations are of great scientific and clinical interest.